Pyrido-/azepino-benzofuran and pyrido-/azepino-benzothiophene mch-1 antagonists, methods of making, and use thereof

a technology of pyridobenzothiophene and azepinobenzothiophene, which is applied in the field of pyrido/azepinobenzofuran and pyrido/azepinobenzothiophene mch1 antagonists, methods of making, can solve the problems of limited efficacy, current available pharmaceutical therapies for the treatment of obesity, and limit their use, so as to increase body mass index, increase waist circum

Inactive Publication Date: 2014-06-12
ALBANY MOLECULAR RESEARCH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0019]It has now been found that compounds of formula I are MCH-1 receptor antagonists. This technology provides compounds that bind to the MCH-1 receptor with high affinity. The compounds provided by formula I are useful for the treatment of obesity, anxiety, depression, psychiatric disorders, and other disorders described herein. In particular, it is contemplated that the compounds described herein will be effective in treating obesity, including weight loss and maintenance of weight loss in patients who have been diagnosed with obesity by the one or more of the following measurements: an increased body mass index, increased waist circumference (an indicator of intra-abdominal fat), Dual Energy X-Ray Absorptiometry (DEXA), and trucal (android) fat mass. It is further contemplated that the compounds described herein will be effective in inducing improvements in certain factors measured in these tests.

Problems solved by technology

The currently available pharmaceutical therapies for the treatment of obesity have limited efficacy and side effects that limit their use.
Obesity has associated with it, economic and social costs.
Moreover, obese persons are more likely to have medical problems associated with or exacerbated by the excess body weight.
Patient compliance, however, is usually poor.
The problem is compounded by the fact that there is currently only a single medication approved for the long term treatment of obesity (orlistat (XENICAL™)).

Method used

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  • Pyrido-/azepino-benzofuran and pyrido-/azepino-benzothiophene mch-1 antagonists, methods of making, and use thereof
  • Pyrido-/azepino-benzofuran and pyrido-/azepino-benzothiophene mch-1 antagonists, methods of making, and use thereof
  • Pyrido-/azepino-benzofuran and pyrido-/azepino-benzothiophene mch-1 antagonists, methods of making, and use thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Analytical Methods and Materials

[0150]Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on Bruker spectrometers at 300, 400 or 500 MHz. Spectra are given in ppm (δ) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Mass spectra were collected using either a Finnigan LCQ Duo LCMS ion trap electrospray ionization (ESI) or a mass Varian 1200L single quadrapole mass spectrometer (ESI). High performance liquid chromatograph (HPLC) analyses were obtained using a Luna C18(2) column (250×4.6 mm, Phenomenex) or a Zorbax Bonus-RP column (150×4.6 mm, 3.5 um, Agilent) with UV detection at 254 nm or 223 nm using a standard solvent gradient program (Method A, Method B or Method C).

Method A:

[0151]

TimeFlow(min)(mL / min)% A% B0.01.0982201.0298251.0298271.0982A = Water with 0.025% Trifluoroacetic AcidB = Acetonitrile with 0.025% Trifluoroa...

example 2

Preparation of 4-(Benzyloxy)-1-(1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridin-7-yl)pyridin-2(1H)-one hydrochloride

a) O-(3-Bromophenyl)hydroxylamine hydrochloride

[0154]CAS Registry Number 937716-47-7

[0155]Potassium hydroxide (7.70 g, 137 mmol) was added to a biphasic solution of 3-bromophenol (19.0 g, 110 mmol) in toluene (27.0 mL), iPrOH (16.4 mL) and H2O (2.67 mL). The resulting suspension was heated at reflux for 1.5 h. A solution of hydroxylamine-O-sulfonic acid (3.10 g, 27.5 mmol) in H2O (16.4 mL) was added dropwise over 20 min to the refluxing solution. The solution was allowed to stir for an additional 15 min. The solution was placed in an ice bath for 5 min. The solution was diluted with 10% NaOH (aq) (100 mL) and with CH2Cl2 (200 mL). The resulting layers were separated, and the aqueous phase was extracted with CH2Cl2 (2×75 mL). The combined organic extracts were washed with 10% NaOH (aq) (7×100 mL), dried over Na2SO4, filtered and partially concentrated under reduced pressure. ...

example 3

Preparation of 4-((5-Fluoropyridin-2-yl)methoxy)-1-(1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridin-7-yl)pyridin-2(1H)-one hydrochloride

a) 4-((5-Fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one

[0164]CAS Registry Number 924311-90-0

[0165]This compound was prepared in accordance with the procedure described in PCT Publication No. WO 2009 / 089482 to Guzzo et al., which is hereby incorporated by reference in its entirety.

b) tert-Butyl 7-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-3,4-dihydrobenzofuro[2,3-c]pyridine-2(1H)-carboxylate

[0166]

[0167]tert-Butyl 7-bromo-3,4-dihydrobenzofuro[2,3-c]pyridine-2(1H)-carboxylate (0.15 g, 0.43 mmol), 4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (0.11 g, 0.51 mmol), and Cs2CO3 (0.18 g, 0.55 mmol) were suspended in toluene (6 mL), and N2 was bubbled through the suspension for 15 min. The suspension was treated with (1S,2S)N,N′-bismethyl-1,2-cyclohexane-diamine (0.10 mL, 0.63 mmol) and bubbled with N2 for 5 min. Copper iodide (0.12 g, 0.63 mmol) ...

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Abstract

Novel MCH-1 receptor antagonists are disclosed. These compounds are used in the treatment of various disorders, including obesity, anxiety, depression, non-alcoholic fatty liver disease, and psychiatric disorders. Methods of making these compounds are also described.

Description

[0001]This application claims the benefit of U.S. Provisional Patent Application Ser. No. 61 / 735,609, filed Dec. 11, 2012, which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION[0002]This technology relates to substituted pyrido- / azepino-benzofurans and pyrido- / azepino-benzothiophenes, which are melanin-concentrating hormone (MCH-1) receptor antagonists, pharmaceutical compositions including these compounds, and methods of preparation and use thereof. The compounds are useful in the treatment of obesity, anxiety, depression, non-alcoholic fatty liver disease, and psychiatric disorders.BACKGROUND OF THE INVENTION[0003]Obesity and the multitude of co-morbidities associated with obesity such as diabetes, dyslipidemia, coronary heart disease, and certain cancers are a major concern for public health. The currently available pharmaceutical therapies for the treatment of obesity have limited efficacy and side effects that limit their use. Thus, there is a signifi...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D491/048C07D491/147A61K31/444A61K31/513A61K31/501A61K31/496A61K45/06C07D495/04A61K31/55
CPCC07D491/048C07D495/04C07D491/147A61K31/444A61K31/55A61K31/501A61K31/496A61K45/06A61K31/513C07D491/18C07D495/18
Inventor SURMAN, MATTHEW D.FREEMAN, EMILY E.GUZZO, PETER R.HENDERSON, ALAN J.HADDEN, MARK
Owner ALBANY MOLECULAR RESEARCH INC
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